The ability to noninvasively detect coronary artery disease (CAD) at a subclinical stage is fundamental to understanding the biology of the transition of occult CAD to clinical CAD in asymptomatic people at the highest risk for future CAD. This study will rigorously compare the pathophysiological features of a functional test for subclinical CAD detection (exercise radionuclide perfusion SPECT) and an anatomical test to detect coronary calcification (ultrafast computed tomography) in a high-risk asymptomatic population of 30-59 year old siblings of people with premature CAD. Siblings will undergo screening for occult CAD using both methods and all who are abnormal on either (exercise-induced ischemia or calcium score >75 th percentile for age and sex) will be offered cardiac catheterization, which will include quantitative coronary angiography, assessment of endothelial function by intracoronary acetylcholine, and measurement of plaque volume and composition in a selected coronary artery by intravascular ultrasound (IVUS). The study will focus on the pathophysiology of occult CAD among individuals who have exercise ischemia with low calcium scores and others who have high calcium scores without ischemia. Discrepancies between these two tests measure potentially different biological pathways and such discrepancies are observed frequently in high-risk asymptomatic siblings (40 percent in our recent pilot study). Analyses will be done to determine which biological risk factors can account for variation in plaque calcification that results in discordances between these two measures of occult disease (including lipid levels and subclasses, Lp(a), diabetes, thrombotic factors, pro-inflammatory cytokincs, and importantly, those factors involved in calcium regulation, and bone regulatory proteins). In those siblings undergoing cardiac catheterization, analyses will be done to determine whether the severity or extent of coronary luminal narrowings, the presence of epicardial or microvascular endothelial dysfunction, or the volume or calcium content of plaque by IVUS can account for discordances between the two screening tests. Polymorphisms in several candidate genes that may affect tissue calcification will be examined as a possible explanation for variations in plaque calcification as reflected in test discordance. Plasma and DNA will also be banked for novel studies of factors that may account for variability in coronary plaque calcification in this unique well-characterized asymptomatic high-risk population. This will be the first comprehensive study to define the unique biological and genetic factors related to occult coronary disease as detected by both perfusion imaging and ultrafast CT. The results of the proposed study will provide a strong scientific underpinning to appropriate clinical application of rapidly disseminating technology and understanding of the mechanisms of preclinical CAD in high-risk asymptomatic populations. [unreadable] [unreadable]